Thiazole or oxazole derivatives which are useful in the treatment of cardiovascular and related diseases

ABSTRACT

A compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrolysable esters thereof 
                 
 
Wherein
     R 1  and R 2  are independently H or C 1-3  alkyl or R 1  and R 2  which are bonded to the same carbon atom may together with the carbon atom to which they are bonded form a 3-5 membered cycloalkyl ring;   X 1  represents O or S;   Each R 3 , R 4 , R 8  and R 9  independently represents H, halogen, —CH 3  and —OCH 3 ;   R 5  represents H or C 1-6  alkyl or R 4  and R 5  together form a 3-6 membered cycloalkyl ring.   

     X 2  represents NH, NCH 3  or O;
     One of Y and Z is N, and the other is O or S;   R 6  represents phenyl or pyridyl (wherein the N is in position 2 or 3) and is optionally substituted by one or more halogen, CF 3 , C 1-6  straight or branched alkyl (optionally substituted by halogen), with the provision that when R 6  is pyridyl, the N is unsubstituted.   

     R 7  represents C 1-6 alkyl, (optionally substituted by one or more halogens), —C 0-8 alkyl-5 membered heteroaryl, C 0-6 alkyl-(O) n -phenyl, wherein n is 0 or 1, with the proviso that when R 1  and R 2  are methyl, R 8  and R 9 are H, R 5  is H, then R 7  cannot be CH 3  or CF 3 .

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/EP02/05885 filed May 29,2002, which claims priority from GB0113233.1 filed May 31, 2001

The present invention relates to certain novel compounds. In particular,the present invention relates to compounds that activate the alphasubtype of the human peroxisome proliferator activated receptor (“hPPARalpha”). The present invention also relates to methods for preparing thecompounds and methods for prevention or treatment of PPAR alpha mediateddiseases or conditions.

Several independent risk factors have been associated withcardiovascular disease. These include hypertension, increased fibrinogenlevels, high levels of triglycerides, elevated LDL cholesterol, elevatedtotal cholesterol, and low levels of HDL cholesterol. HMG CoA reductaseinhibitors (“statins”) are useful for treating conditions characterizedby high LDL-c levels. It has been shown that lowering LDL-c is notsufficient for reducing the risk of cardiovascular disease in somepatients, particularly those with normal LDL-c levels. This populationpool is identified by the independent risk factor of low HDL-c. Theincreased risk of cardiovascular disease associated with low HDL-clevels has not yet been successfully addressed by drug therapy (i.e.,currently there are no drugs on the market that are useful for raisingHDL-c >40%). (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4,53-70).

Syndrome X (including metabolic syndrome) is loosely defined as acollection of abnormalities including hyperinsuinlemia, obesity,elevated levels of trigycerides, uric acid, fibrinogen, small denseLDL-c particles, and plasminogen activator inhibitor 1 (PAI-1), anddecreased levels of HDL-c.

NIDDM is described as insulin resistance which in turn causes anomalousglucose output and a decrease in glucose uptake by skeletal muscle.These factors eventually lead to impaired glucose tolerance (IGT) andhyperinsulinemia.

Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptorsbelonging to the steroid/retinoid receptor superfamily ofligand-activated transcription factors. See, for example, Willson, T. M.and Wahli, W., Curr. Opin. Chem. Biol., (1997), Vol. 1, pp 235-241.

Three mammalian Peroxisome Proliferator-Activated Receptors have beenisolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also knownas NUC1 or PPAR-beta). These PPARs regulate expression of target genesby binding to DNA sequence elements, termed PPAR response elements(PPRE). To date, PPRE's have been identified in the enhancers of anumber of genes encoding proteins that regulate lipid metabolismsuggesting that PPARs play a pivotal role in the adipogenic signalingcascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrin.Met 291-296, 4 (1993)).

Certain compounds that activate or otherwise interact with one or moreof the PPARs have been implicated in the regulation of triglyceride andcholesterol levels in animal models. See, for example, U.S. Pat. No.5,847,008 (Doebber et al.) and U.S. Pat. No. 5,859,051 (Adams et al.)and PCT publications WO 97/28149 (Leibowitz et al.) and WO99/04815(Shimokawa et al.).

Fibrates are a class of drugs which may lower serum triglycerides20-50%, lower LDL-c 10-15%, shift the LDL particle size from the moreatherogenic small dense to normal dense LDL-c, and increase HDL-c10-15%. Experimental evidence indicates that the effects of fibrates onserum lipids are mediated through activation of PPAR alpha. See, forexample, B. Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997).Activation of PPAR alpha results in transcription of enzymes thatincrease fatty acid catabolism and decrease de-novo fatty acid synthesisin the liver resulting in decreased triglyceride synthesis and VLDL-cproduction/secretion. In addition, PPAR alpha activation decreasesproduction of apoC-III. Reduction in apoC-III, an inhibitor of LPLactivity, increases clearance of VLDL-c. See, for example, J. Auwerx etal., Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).PPAR alpha ligands may be useful for the treatment of dyslipidemia andcardiovascular disorders, see Fruchart, J. C., Duriez, P., and Staels,B., Curr. Opin. Lipidol. (1999), Vol 10, pp 245-257.

According to a first aspect of the invention there is provided acompound of formula (I) and pharmaceutically acceptable salts, solvatesand hydrolysable esters thereof:

Wherein

R¹ and R² are independently H or C₁₋₃ alkyl or R¹ and R² which arebonded to the same carbon atom may together with the carbon atom towhich they are bonded form a 3-5 membered cycloalkyl ring;

X₁ represents O or S;

Each R³, R⁴, R⁸ and R⁹ independently represents H, halogen, —CH₃ or—OCH₃;

R⁵ represents H or C₁₋₆ alkyl or R⁴ and R⁵ together form a 3-6 memberedcycloalkyl ring.

X₂ represents NH, NCH₃ or O;

One of Y and Z is N, and the other is O or S;

R⁶ represents phenyl or pyridyl (wherein the N is in position 2 or 3)and is optionally substituted by one or more halogen, CF₃, C₁₋₆ straightor branched alkyl (optionally substituted by halogen), with theprovision that when R⁶ is pyridyl, the N is unsubstituted.

R⁷ represents C₁₋₆alkyl, (optionally substituted by one or morehalogens), —C₀₋₆alkyl- 5 membered heteroaryl, C₀₋₆alkyl —(O)_(n)—phenyl, wherein n is 0 or 1 with the proviso that when R¹ and R² aremethyl, R⁸ and R⁹ are H, R⁵ is H, then R⁷ cannot be CH₃ or CF₃.

In another aspect, the present invention discloses a method forprevention or treatment of a human PPAR (“hPPAR”) mediated diseases orconditions comprising administration of a therapeutically effectiveamount of a compound of this invention. hPPARmediated diseases orconditions include dyslipidemia including associated diabeticdyslipidemia and mixed dyslipidemia, syndrome X (as defined in thisapplication this embraces metabolic syndrome), heart failure,hypercholesteremia, cardiovascular disease including atherosclerosis,arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus,type I diabetes, insulin resistance, hyperlipidemia, inflammation,epithelial hyperproliferative diseases including eczema and psoriasisand conditions associated with the lining and gut and regulation ofappetite and food intake in subjects suffering from disorders such asobesity, bulimia, and anorexia nervosa. In particular, the compounds ofthis invention are useful in the treatment and prevention ofcardiovascular diseases and conditions including atherosclerosis,arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, preferably inassociation with a pharmaceutically acceptable diluent or carrier.

In another aspect, the present invention provides a compound of theinvention for use in therapy, and in particular, in human medicine.

In another aspect, the present invention provides the use of a compoundof the invention for the manufacture of a medicament for the treatmentof a hPPAR mediated disease or condition.

In another aspect, the present invention provides a method of treatmentof a patent suffering from a hPPAR mediated disease or conditioncomprising the administration of a therapeutically effective amount of acompound of the invention.

As used herein, “a compound of the invention” means a compound offormula (I) or a pharmaceutically acceptable salt, solvate, orhydrolyzable ester thereof.

While hydrolyzable esters are included in the scope of this invention,the acids are preferred because the data suggests that while the estersare useful compounds, it may actually be the acids to which theyhydrolyze that are the active compounds. Esters that hydrolyze readilycan produce the carboxylic acid in the assay conditions or in vivo.Generally the carboxylic acid is active in both the binding andtransient transfection assays, while the ester does not usually bindwell but is active in the transient transfection assay presumably due tohydrolysis. Preferred hydrolysable esters are C₁₋₆ alkyl esters whereinthe alkyl group may be straight chain or branched chain. Methyl or ethylesters are more preferred.

Preferably X₁ represents O.

Preferably R¹ and R² are methyl.

Preferably R³ is methyl or H.

Preferably R⁴ is H or together with R⁵ forms a 6 membered cycloalkylring.

Preferably R⁸ and R⁹ both represent H.

Preferably R⁵ represents CH₃, H or together with R⁴ forms a 6 memberedcycloalkyl ring.

Preferably X₂ represents NH.

Preferably Z represents N.

Preferably Y represents S.

Preferably R⁷ represents CH₃—CH₂—O-phenyl, or CH₂—O-thiophene (whereinthe S is in position 2).

Preferably R⁶ is phenyl, optionally substituted. Preferably R⁶ is monoor disubstituted. Preferably when R⁶ is pyridyl the N is in the 2position. R⁶ preferably is monosubstituted in the para position and ismore preferably phenyl. A preferred substituent is CF₃.

While the preferred groups for each variable have generally been listedabove separately for each variable, preferred compounds of thisinvention include those in which several or each variable in Formula (I)is selected from the preferred, more preferred, or most preferred groupsfor each variable. Therefore, this invention is intended to include allcombinations of preferred, more preferred, and most preferred groups.

Preferably, the compounds of formula (I) are hPPAR agonists. The hPPARagonists of formula (I) may be agonists of only one type (“selectiveagonists”), agonists for two PPAR subtypes (“dual agonists”), oragonists for all three subtypes (“pan agonists”). As used herein, by“agonist”, or “activating compound”, or “activator”, or the like, ismeant those compounds which have a pKi of at least 6.0 preferably atleast 7.0 to the relevant PPAR, for example hPPAR delta, in the bindingassay described below, and which achieve at least 50% activation of therelevant PPAR relative to the appropriate indicated positive control inthe transfection assay described below at concentrations of 10-5 M orless. More preferably, the compounds of this invention achieve 50%activation of at least one human PPAR in the relevant transfection assayat concentrations of 10-6 M or less. More preferably the compounds ofthe invention achieve 50% activation of at least one human PPAR in therelevant transfection assay at concentrations of 10-7M or less.

Preferably the compounds are hPPAR alpha agonists.

Most preferably, the compounds of formula (I) are selective hPPAR alphaagonists. As used herein, a “selective hPPAR alpha agonist” is a hPPARalpha agonist whose EC₅₀ for PPAR alpha is at least 10 fold lower thanits EC₅₀ for PPAR gamma and PPAR delta. Such selective compounds may bereferred to as “10-fold selective.” EC₅₀ is defined in the transfectionassay described below and is the concentration at which a compoundachieves 50% of its maximum activity. Most preferred compounds aregreater than 100-fold selective hPPAR alpha agonists.

Preferred compounds of the invention include:

2-methyl-2-[3-methyl-4-{[(4-phenoxymethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester

2-methyl-2-[3-methyl-4-{[(4-phenoxymethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid

2-methyl-2-[3-methyl-4-{[(4-thiophen-2-ylmethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester

2-methyl-2-[3-methyl-4-{[(4-thiophen-2-ylmethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid

2-Methyl-2-[5-{[(4-Methyl-2-[4-trifluoromethyl-phenyl]-thiazol-5-ylcarbonyl)amino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]propionic acid ethyl ester

2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionicacid ethyl ester

More preferred compound of the invention is:

2-Methyl-2-[5-{[(4-Methyl-2-[4-trifluoromethyl-phenyl]-thiazol-5-ylcarbonyl)amino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]propionic acid

Most preferred compound of the invention is:

2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionicacid

The preferred compounds listed above are selective hPPAR alpha agonists.

Those skilled in the art will recognize that stereocenters exist incompounds of formula (I). Accordingly, the present invention includesall possible stereoisomers of formula (I) and includes not only racemiccompounds but this invention is also intended to cover each of theseisomers in their racemic, enriched, or purified forms. When a compoundof formula (I) is desired as a single enantiomer, it may be obtainedeither by resolution of the final product or by stereospecific synthesisusing an optically active catalyst or a catalytic system with opticallyactive ligands or isomerically pure starting material or any convenientintermediate. Resolution of the final product, an intermediate or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Carbon Compounds by E. L.Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen.Additionally, in situations where tautomers of the compounds of formula(I) are possible, the present invention is intended to include alltautomeric forms of the compounds. In particular, in many of thepreferred compounds of this invention the carbon atom to which R¹ and R⁵are bonded is chiral. In some of these chiral compounds the activitiesat the various PPAR receptors varies between the S and R isomers. Whichof these isomers is preferred depends on the particular desired utilityof the compound. In other words, even with the same compound, it ispossible that the S isomer will be preferred for some uses, while the Risomer will be preferred for others.

It will also be appreciated by those skilled in the art that thecompounds of the present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. The physiologicallyacceptable salts of the compounds of formula (I) include conventionalsalts formed from pharmaceutically acceptable inorganic or organic acidsor bases as well as quaternary ammonium acid addition salts. Morespecific examples of suitable acid salts include hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic,propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric,palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts. Referenceshereinafter to a compound according to the invention include bothcompounds of formula (I) and their pharmaceutically acceptable salts andsolvates.

The compounds of the invention and their pharmaceutically acceptablederivatives are conveniently administered in the form of pharmaceuticalcompositions. Such compositions may conveniently be presented for use inconventional manner in admixture with one or more physiologicallyacceptable carriers or excipients.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalformulation comprising a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof together with one or morepharmaceutically acceptable carriers therefore and, optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association the compounds (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets (e.g. chewabletablets in particular for paediatric administration) each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with aother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, hard fat or polyethyleneglycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms. Moreover, it will be appreciated thatthe amount of a compound of the invention required for use in treatmentwill vary with the nature of the condition being treated and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician or veterinarian. In general, however, dosesemployed for adult human treatment will typically be in the range of0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day. The formulations according to the inventionmay contain between 0.1-99% of the active ingredient, conveniently from30-95% for tablets and capsules and 3-50% for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, statins and/orother lipid lowering drugs for example MTP inhibitors and LDLRupregulators. The compounds of the invention may also be used incombination with antidiabetic agents, e.g. metformin, sulfonylureasand/or PPAR gamma agonists (for example thiazolidinediones such as e.g.Pioglitazone and Rosiglitazone). The compounds may also be used incombination with antihypertensive agents such as calcium channelantagonists and ACE inhibitors. The invention thus provides in a furtheraspect the use of a combination comprising a compound of formula (I)with a further therapeutic agent in the treatment of a hPPAR alphamediated disease.

When the compounds of formula (I) are used in combination with othertherapeutic agents, the compounds may be administered eithersequentially, or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optimallytogether with a pharmaceutically acceptable carrier or excipientcomprise a further aspect of the invention. The individual components ofsuch combinations may be administered either sequentially orsimultaneously in separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, conveniently in such a manner as are known forsuch compounds in the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the same hPPAR mediated disease, thedose of each compound may differ from that when the compound is usedalone. Appropriate doses will be readily appreciated by those skilled inthe art.

Compounds of this invention may be conveniently prepared by a generalprocess wherein a moiety like (A) is coupled to an acid (B) using apeptide coupling reaction. Note that this synthesis may be carried outwith the acid group protected by R. Preferably, R is C₁₋₆alkyl which canbe hydrolyzed off to give an acid of Formula (I), or if readilyhydrolyzable, the resulting ester can be administered.

Compounds of formula (A) and (B) may be commercially available or theirsynthesis will be apparent to a skilled person, eg by analogous methodsto those described below.

The invention is further illustrated by the following examples whichshould not be construed as constituting a limitation thereto.

Intermediate 1:

A solution of ethyl 2-chloroacetoacetate (35.3 g, 29.7 mL, 0.21 mol) and4-(trifluoromethyl)thiobenzamide (44 g, 0.21 mol) in EtOH (300 mL) wasrefluxed overnight. After cooling to room temperature the solvent wasremoved in vacuo. The final product (intermediate 1) was recrystallizedfrom a minimum of MeOH to afford 40 g (59%) of final product as a whitesolid. ¹H NMR (CDCl₃): δ8.10 (d, 2H), 7.70 (d, 2H), 4.40 (q, 2H), 2.80(s, 3H), 1.4 (t, 3H).

Intermediate 2:

To a solution of intermediate 1 (15.75 g, 50 mmol) in 250 mL of CCl₄ isadded NBS (1.96 g, 11 mmol). To the resulting suspension is added AIBN(1 g) and the mixture is heated to 80° C. for 3 hours then filtered offand concentrated under vacuo. The residue is taken up in CH₂Cl₂ (500 mL)and washed with brine (100 mL). The organic layer is dried over Na₂SO₄,filtered and concentrated to dryness to afford after columnchromatography eluting with CH₂Cl₂/C₆H₁₂ (40/60) the title compound(73%).

GC/MS: m/z: 393-395

Intermediate 3:

To a solution of Intermediate 2 (394 mg, 1 mmol) in 25 mL of acetone areadded Phenol (100 mg, 1.1 mmol) and Cs₂CO₃ (355 mg, 1.1 mmol). Theresulting mixture is heated at 50° C. for 12 hours. After filtration,concentration under vacuum the residue is taken up with CH₂Cl₂ (100 mL)and washed with NaOH 0.1N (10 mL). The organic layer is dried overNa₂SO₄, filtered, concentrated to dryness to give the title compound asa white solid (94%). ¹H NMR (CDCl₃): δ8.05 (d, 2H), 7.65 (d, 2H), 7.2(m, 2H), 7.0 (d, 2H), 6.9 (t, 1H), 5.45 (s, 2H), 4.25 (q, 2H), 1.25 (t,3H).

Intermediate 4:

To a solution of Intermediate 2 (1 g, 2.5 mmol) in 50 mL of DME under anitrogen atmosphere are added (87 mg, 0.075 mmol) of Pd(PPh₃)₄. Afterheating at 50° C. for 20 minutes a solution of 2-thienyl boronic acid(480 mg, 3.75 mmol) in a mixture of EtOHt DME (20 mL/20 mL) is addedfollowed by a solution of 2M Na₂CO₃ (5 mL). After stirring at 50° C. for18 hours , extraction is done (×3) with CH₂Cl₂ (150 mL). The combinedorganic layers are dried over Na₂SO₄, filtered and concentrated todryness. T.I.c. and ¹H NMR monitoring of this crude mixture indicatethat it stll remains starting intermediate 3. Stirring overnight of thecrude product in DMF (10 mL) with PS-Triphenylphosphine (1 g, 1-1.5mmol/g, Argonaut) allows the trapping of the bromide derivative. Afterfiltration and concentration under vacuum the title compound is obtainedas a pale yellow oil (33%).

GC/MS: m/z 397.

Intermediate 5:

To 4-methoxy-3-methylbenzaldehyde (1 equiv., Acros) in EtOH (150 mL) atrt was added H₂NOH,HCl (1.6 equiv.), (3 equiv.) NaOAc in 150 mL H₂O andthe reaction stirred for 2 h. The EtOH was evaporated, and the residueextracted with CH₂Cl₂ (3×50 mL). The combined organic layers were washedwith H₂O, dried over Na₂SO₄, filtered and evaporated to dryness toafford the title compound as a white solid (93%).

Mp 71-73° C.

Intermediate 6:

To intermediate 5 (1 equiv.) in MeOH (200 mL) at rt was added HCO₂NH₄ (6equiv.), Pd/C (0.01 equiv.) and molecular sieves. The reaction was thenheated to reflux for 18 h. The reaction was filtered through celite,evaporated to dryness and treated with HCl (1N). The aqueous layer waswashed with CH₂Cl₂, filtered, basified to pH >14 and extracted withCH₂Cl₂ (3×50 mL). The combined organic,layers were washed with H₂O,dried over Na₂SO₄, filtered and evaporated to dryness to afford thetitle compound as an oil (46%).

MS m/z 151

Intermediate 7:

Intermediate 6 (1 equiv.) in excess 40% HBr/H₂O (Aldrich) was refluxedfor 18 h. The reaction was then evaporated to dryness to afford thetitle compound hydrobromide salt as a grey solid (97%).

Mp 235-237° C.

Intermediate 8:

To Intermediate 7 (1 equiv.) in CH₂Cl₂ (300 mL) at 0° C. was added Et₃N(3 equiv.). Boc anhydride (0.95 equiv.) in CH₂Cl₂ (50 mL) was addeddropwise. The reaction was allowed to warm to rt and stirring continuedfor 18 h. HCl (1N) was added and the reaction extracted with CH₂Cl₂(3×100 mL). The organic layers washed with H₂O, dried over Na₂SO₄,filtered and the solvent removed under vaccum to afford the titlecompound as a white solid (96%).

Mp 105-107° C.

Intermediate 9:

To intermediate 8 (1 equiv.) in DMF (150 mL) was added K₂CO₃ (3 equiv.)and the reaction heated to 70° C. Ethyl 2-bromo-2-methylproprionate (1.3equiv.) was added droppwise and the reaction was stirred for 72 h at 70°C. The reaction was poured onto ice and extracted with CH₂Cl₂ (3×150mL). The combined organic layers were washed with NaOH (0.5N), then H₂Oand dried over Na₂SO₄. The solution was filtered, evaporated to drynessto afford the title compound as an oil (69%). ¹H NMR (CDCl₃): δ7.05 (d,1H), 6.90 (dd, 1H), 6.60 (d, 1H), 4.80 (bs, 1H), 4.25 (q, 2H), 4.20 (d,2H), 2.20 (s, 3H), 1.60 (s, 6H), 1.45 (s, 9H), 1.25 (t, 3H).

Intermediate 10:

To intermediate 9 (1 equiv.) in CH₂Cl₂ (10 mL) at rt was added dropwiseCF₃COOH (7 equiv.) and the reaction stirred at rt for 18 h. The reactionwas evaporated to dryness, treated with a sat. K₂CO₃ solution andextracted with CH₂Cl₂ (3×150 mL). The combined organic layers were driedover Na₂SO₄, filtered and evaporated to dryness to afford the titlecompound as an oil (82%). ¹H NMR (CDCl₃): δ7.00 (d, 1H), 6.90 (dd, 1H),6.55 (d, 1H), 4.20 (q, 2H), 3.70 (s, 2H), 2.15 (s, 3H), 1.85 (bs, 2H),1.50 (s, 6H), 1.20 (t, 3H).

Intermediate 11:

To a solution of 4-hydroxy-3′-methyl-acetophenone (50 g; 0.33 mol) in1.5 L of acetone is added Cesium carbonate (216.9 g, 0.66 mol). Afterstirring to reflux for 30 minutes ethyl-2-bromoisobutyrate is added (97mL, 0.66 mol) to the mixture and the reflux maintained. The samequantities as above of cesium carbonate and ethylbromoisobutyrate areadded in two times to complete the reaction. The mixture is thenfiltered and after concentration to dryness the residue is taken up with2 L of CH₂Cl₂ and washed 3 times with water (500 mL). The organic layersare combined and dried over Na₂SO₄, filtered and concentrated undervacuo to afford the title compound as a brown oil (87%). ¹H NMR (CDCl₃):δ7.71 (s, 1H), 7.61 (d, 1H), 6.5 (d,1H), 4.15 (q, 2H), 2.45 (s, 3H),2.20 (s, 3H), 1.58 (s, 6H), 1.15 (t, 3H)

Intermediate 12:

To a solution of Intermediate 11 (7.55 g, 28.6 mmol) is addedhydroxylamine hydrochloride (3.2 g, 45.76 mmol) and sodium acetate (7 g,85.8 mmol) in solution in water (75 mL). After stirring at roomtemperature for 6 hours EtOH is removed under reduced pressure and theresidue taken up with CH₂Cl₂ (500 mL) and washed with water (100 mL).The organic layer is dried over Na₂SO₄, filtered and concentrate todryness to afford the title compound (96%) as an oil.

¹H NMR (CDCl₃): δ7.30 (s, 1H), 7.2 (d, 1H), 6.55 (d, 1H), 4.15 (q, 2H),2.15 (s, 6H), 1.55 (s, 6H), 1.15 (t, 3H).

Intermediate 13:

To a solution of intermediate 12 (7.7 g, 27.6 mmol) in MeOH (150 mL)under a nitrogen atmosphere are added ammonium formiate (10.4 g, 166mmol) and 10% Pd/C (700 mg). The mixture is heated to reflux for 24hours and filtered on a celite pad. After washing with MeOH (100 mL) thefiltrate is concentrated under vacuum and the residue taken up withCH₂Cl₂ (250 mL) and 1N HCl (250 mL). The aqueous layer is separated andbasified to pH=14 with 35% NaOH. Extraction is then carried out withCH₂Cl₂ (300 mL) and the organic layer is dried over Na₂SO₄, filtered andconcentrated to dryness to afford the expected compound as a colorlessoil (57%).

MS: m/z 265

Intermediate 14:

6-hydroxy-1-tetralone (20 g; 0.125 mol) and potassium carbonate (28 g;0.2 mol) were stirred at room temperature in 250 mL ofMethylisopropylketone during 15 minutes. Ethylbromoisobutyrate (20mL;0.13 mol) was added and the mixture was refluxed 10 hours withstirring. The mixture was filtrated, concentrated, treated with waterand extracted with diethyl ether. The ethereal solution was washed withdiluted sodium hydroxide, water, dried over Na₂SO₄ and concentratedunder vacuo to give the title compound (42%) as an oil.

MS:m/z 276

Intermediate 15:

To a solution of Intermediate 14 (2 g; 7.2 mmol) in 50 mL of Ethanol wasadded a solution of hydroxylamine hydrochloride (1 g; 15 mmol) in water(5 mL), followed by sodium acetate (1.2 g; 15 mmol). The mixture wasstirred at reflux during 16 hours. The mixture was then concentrated todryness and heated with water to give an oil which crystallized uponstanding. After filtration, washing with water and drying, the titlecompound was obtained as cream crystals (81%).

Mp 80° C.

MS: m/z 291

Intermediate 16:

A mixture of Intermediate 15 (1.6 g; 5.5 mmol) in 100 mL of Ethanol and10% Pd/C (0.2 g) was hydrogenated 16 hours at 50° C. in a Parr apparatusunder a pressure of 30 bars. After filtration through a celite pad andconcentration under vacuo, the title compound is obtained as an oil(79%). ¹H NMR (CDCl₃): δ7.15 (d, 1H), 6.55 (d, 1H), 6.45 (s, 1H), 4.15(q, 2H), 3.9 (m, 1H) 2.65 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H), 1.65(m,2H), 1.5 (s,6H), 1.2 (t,3H)

General Procedure 1 for the Hydrolysis of the Ethyl Esters

To a solution of the ethyl ester (1 mmol) in MeOH (50 mL) was added (3equiv.) NaOH (1N) and the mixture heated to 60° C. overnight. Thereaction is cooled to room temperature and the solution acidified withHCl (1N) and extracted with CH₂Cl₂ (3×25 mL). The combined organiclayers washed with H₂O, dried over Na₂SO₄, filtered and evaporated todryness. The solid was titrated with Et₂O, collected and dried undervaccum to afford the final product.

Intermediate 17:

Intermediate 1 was reacted as described in general procedure 1 to affordintermediate 17 (89%) as a white solid. ¹H NMR (DMSO-d₆): δ13.55 (bs,1H), 8.25 (d, 2H), 7.95 (d, 2H), 2.75 (s, 3H).

Intermediate 18:

Intermediate 3 was reacted as described in general procedure 1. Afterremoval of EtOH under reduced pressure, the residue was treated with HCland the solid collected, washed with water and dried under vacuum toafford a white powder (86%). ¹H NMR (CDCl₃): δ8.05 (d, 2H), 7.65 (d,2H), 7.2 (m, 2H), 6.95 (d, 2H), 6.9 (t, 1H), 5.45 (s, 2H).

Intermediate 19:

Intermediate 4 (330 mg, 0.85 mmol) was reacted as described in generalprocedure 1. After removal of EtOH under reduced pressure, the residuewas taken up with EtOAc (150 mL) , the aqueous phase acidified to pH=1with HCl 1N. The organic layer is dried over Na₂SO₄, filtered andconcentrated to dryness to afford after column chromatography elutingwith CH₂Cl₂/MeOH (85/15) the title compound (98%) as an off-white solid.

MS (AP+): 369.88 (M+1)

General Procedure 2 for the Peptide Coupling Reaction betweenIntermediates of Type A and B

To intermediate B (1 equiv.) in CH₂Cl₂ (75 mL) at rt was added HOBT (1.1equiv.), EDC (1.1 equiv.) and Et₃N (3 equiv.). To the mixture was addedintermediate A and the reaction was stirred at rt for 18 h. The reactionwas washed with HCl (1N), NaOH (1N) and 2×H₂O. The organic layer wasdried over Na₂SO₄, filtered and evaporated to dryness. The crudecompound was chromatographed or crystallized as necessary to afford thefinal product.

General Procedure 3 for the Peptide Coupling Reaction betweenIntermediates of Type A and B

To intermediate B (1 equiv.) in DMF (25 mL) at rt was added HATU (1.1equiv.), intermediate A (1 equiv.) and Et₃N (2 equiv.). The reaction wasstirred at rt for 18 h. The mixture is evaporated to dryness undervacuum and the residue is taken up in 200 mL of CH2Cl2 and washed withbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness. The crude compound was chromatogaphed orcrystallized as necessary to afford the final product.

EXAMPLE 1

2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionicacid ethyl ester

Intermediate 22 and intermediate 5 were reacted as described in generalprocedure 3 to afford the title compound as a white solid (94%).Chromatographed: CH₂Cl₂/EtOAc (93/7)

Mp 116° C.

MS(AP+): 535.35 (M+1)

EXAMPLE 2

2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionicacid

Example 1 was reacted as described in general procedure 1. Afterchromatography eluting with CH₂Cl₂/MeOH (95:5) the title compound wasobtained from a recrystallization in toluene as a white solid (63%).MS(AP−): 505.1 (M−1)

EXAMPLE 3

2-Methyl-2-[5-{[(4-Methyl-2-[4-trifluoromethyl-phenyl]-thiazol-5-ylcarbonyl)amino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]propionicacid ethyl ester

Intermediate 19 and Intermediate 2 were reacted as described in generalprocedure 2 to afford the title compound as a white solid afterrecrystallization with acetonitrile (74%).

Mp 142° C.

EXAMPLE 4

2-Methyl-2-[5-{[(4-Methyl-2-[4-trifluoromethyl-phenyl]-thiazol-5-ylcarbonyl)amino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]propionicacid

Example 3 was reacted as described in general procedure 1. The titlecompound was obtained as a white powder (67%) from recrystallization inacetonitrile.

Mp 158-160° C.

EXAMPLE 5

2-methyl-2-[3-methyl-4-{[(4-phenoxymethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester

Intermediate 19 and intermediate 5 were reacted as described in generalprocedure 2 to afford the title compound as a yellow oil (66%).Chromatographed: C₆H₁₂/EtOAc (80/20)

MS(AP−): 611.2 (M−1)

MS(AP+): 613.1 (M+1)

EXAMPLE 6

2-methyl-2-[3-methyl-4-{[(4-phenoxymethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid

Example 5 was reacted as described in general procedure 1. Afterchromatography eluting with CH₂Cl₂/MeOH (96:4) the title compound wasobtained from recrystallization in hexane as a pale yellow powder (57%).

Mp 146° C.

MS(AP−): 583.1 (M−1)

MS(AP+): 585 (M+1)

EXAMPLE 7

2-methyl-2-[3-methyl-4-{[(4-thiophen-2-ylmethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester

Intermediate 7 and intermediate 19 were reacted as described in generalprocedure 3 to afford the title compound as a colorless gum (49%).Chromatographed: CH₂Cl₂/EtOAc (90/10)

MS(AP−): 601.03 (M−1)

MS(AP+): 602.92 (M+1)

EXAMPLE 8

2-methyl-2-[3-methyl-4-{[(4-thiophen-2-ylmethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid

Example 7 was reacted as described in general procedure 1. Afterchromatography eluting with CH₂Cl₂/MeOH (95:5) the title compound wasobtained from consecutive recrystallizations in hexane and toluene as awhite powder (23%).

Mp 147° C.

MS(AP−): 573.1 (M−1)

Binding Assay:

Compounds were tested for their ability to bind to hPPAR gamma hPPARalpha or PPAR delta using a Scintillation Proximity Assay (SPA). ThePPAR ligand binding domain (LBD) was expressed in E. coli as polyHistagged fusion proteins and purified. The LBD was then labeled withbiotin and immobilized on streptavidin-modified scintillation proximitybeads. The beads were then incubated with a constant amount of theappropriate radioligand (³H-BRL 49653 for PPAR gamma, radiolabelled2-(4-(2-(2,3-Ditritio-1-heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid for hPPAR alpha (see WO 00/08002) and labelled GW 2433 for PPARdelta (see Brown, P. J et al . Chem. Biol. 1997, 4, 909-918 for thestructure and synthesis of this ligand and variable concentrations oftest compound, and after equilibration the radioactivity bound to thebeads was measured by a scintillation counter. The amount of nonspecificbinding, as assessed by control wells containing 50 μM of thecorresponding unlabeled ligand, was subtracted from each data point. Foreach compound tested, plots of ligand concentration vs. CPM ofradioligand bound were constructed and apparent K, values were estimatedfrom nonlinear least squares fit of the data assuming simple competitivebinding. The details of this assay have been reported elsewhere (see,Blanchard, S. G. et. al. Development of a Scintillation Proximity Assayfor Peroxisome Proliferator-Activated Receptor gamma Ligand BindingDomain. Anal. Biochem. 1998, 257, 112-119).

Transfection Assay:

(i)2-2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid.

This compound was used as a PPARdelta reference in the transfectionassays described below and was prepared according to the method reportedin WO200100603-A1

(ii) 2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid.

This compound was used as a PPAR alpha reference in the transfectionassay described below and was prepared according to method reported inWO200140207-A1 (and reproduced below).

Intermediate (a):

Same procedure as Stout, D. M. J. Med. Chem. 1983, 26(6), 808-13. To4-methoxybenzyl amine (25 g, 0.18 mol; Aldrich) was added 46% HBr in H₂O(106 ml, 0.9 mol; Aldrich). The reaction was refluxed overnight, thenthe reaction cooled to 0° C. and neutralized to pH7 slowly withKOH_((s)). The reaction is allowed to stir for ≈30 min, then the solidfiltered and dried. The solid redisolved in hot MeOH, filtered and thesolution cooled to afford 19 g (85%) intermediate 1. ¹H NMR (DMSO-d₆):δ8.0 (bs, 1H), 7.2 (d, 2H), 6.75 (d, 2H), 3.85 (s, 2H), 3.50 (bs, 2H).

Intermediate (b):

A solution of ethyl 2-chloroacetoacetate (35.3 g, 29.7 mL, 0.21 mol) and4-(trifluoromethyl)thiobenzamide (44 g, 0.21 mol) in EtOH (300 mL) wasrefluxed overnight. After cooling to room temperature the solventremoved in vacuo. The final product (intermediate (b)) wasrecrystallized from a minimum of MeOH to afford 40 g (59%) of finalproduct as a white solid. ¹H NMR (CDCl₃): δ8.10 (d, 2H), 7.70 (d, 2H),4.40 (q, 2H), 2.80 (s, 3H), 1.4 (t, 3H).

Intermediate (c):

To intermediate (b) (1.84 g, 5.8 mmol) in THF was added 1N LiOH (6 mL, 6mmol) and the reaction stirred at rt. After ˜3 h, the reactionneutralized with 1N HCl, extracted 3×100 mL EtOAc, dried over Na₂SO₄,filtered and the solvent removed under vaccum to afford 1.5 g (89%)intermediate (b) as a white solid. ¹H NMR (DMSO-d₆): δ13.55 (bs, 1H),8.25 (d, 2H), 7.95 (d, 2H), 2.75 (s, 3H).

Intermediate (d):

To intermediate (c) (1 g, 7 mmol) in CH₂Cl₂/DMF (1:1) was added HOBT(565 mg, 4.2 mmol; Aldrich), EDC (800 mg, 4.2 mmol; Aldrich) andintermediate 1 (860 mg, 7 mmol). The reaction stirred at rt for 18 h.The solvent removed in vacuo, treated with H₂O and extracted 3×100 mLCH₂Cl₂. The organic phases combined and washed with 1N HCl, dried overNa₂SO₄, filtered and evaporated to afford a mixture (N-substituted andN,O-substituted). The mixture disolved in MeOH and treated with 1N NaOH.The reaction stirred 18 h at 50° C. The solvent removed in vacuo,dissolved in CH₂Cl₂, washed with H₂O, and dried over Na₂SO₄. The solventevaporated the residue chromatographed (CH₂Cl₂/MeOH: 99/1) to afford 610mg (47%) of intermediate 6 as a white solid. ¹H NMR (DMSO-d₆): δ9.30 (s,1H), 8.80 (t, 1H), 8.20 (d, 2H), 6.70 (d, 2H), 4.35 (d, 2H), 2.6 (s,3H).

Intermediate (e):

2-methyl-2-[4{[(4-methyl-2-[4-trifluoromethylphenyl]thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester

To intermediate (d) (710 mg, 1.81 mmol) in DMF (50 mL) was added theK₂CO₃ (275 mg, 1.99 mmol) followed by the ethyl2-bromo-2-methylpropanate (280 μL, 1.91 mmol; Aldrich) and the reactionheated to 80° C. After 18 h, the reaction cooled to rt and the solventremoved in vacuo. The residue treated with water (200 mL), extracted3×50 mL CH₂Cl₂, dried over Na₂SO₄, filtered and the solvent removedunder vaccum. The residue was chromatographed (CH₂Cl₂/MeOH: 99/1). Toafford 680 mg (77%) of Example 1 as a clear oil. ¹H NMR(CDCl₃): δ7.95(d, 2H), 7.60 (d, 2H), 7.15 (d, 2H), 6.75 (d, 2H), 6.05 (t, 1H), 4.45(d, 2H), 4.15 (q, 2H), 2.65 (s, 3H), 1.50 (s, 6H), 1.20 (t, 3H).

2-methyl-2-[4{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid

To Intermediate (e) (680 mg, 1.39 mmol) in MeOH was added 1N NaOH (1.6mL, 1.6 mmol) and the reaction stirred at 60° C. After 18 h, thereaction cooled to rt and the solvent evaporated. The residue treatedwith 1N HCl, extracted 3×20 mL THF and the solvent removed under vacuum.500 mg (75%) the title compound was precipitated as a white solid from aminimum CH₂Cl₂ and pentane. mp: changes the form between 60-70° C.;LC/MS (m/z): 477.22 (100%, AP−), 479.12 (100%, AP+); anal.C₂₃H₂₁F₃N₂O₄S: C 5.71 (57.73), H 4.56 (4.42), N 5.77 (5.85), S 6.15(6.70).

(iii)5-{4-[2-(Methyl-pyridin-2-yl-amino)-ethoxy]-benzyl}-thiazolidine-2,4-dione

This compound was used as a PPAR gamma reference in the transfectionassay described below and was prepared according to method reported inJ. Med. Chem. 1994, 37(23), 3977

Compounds were screened for functional potency in transient transfectionassays in CV-1 cells for their ability to activate the PPAR subtypes(transactivation assay). A previously established chimeric receptorsystem was utilized to allow comparison of the relative transcriptionalactivity of the receptor subtypes on the same target gene and to preventendogenous receptor activation from complicating the interpretation ofresults. See, for example, Lehmann, J. M.; Moore, L. B.; Smith-Oliver,Oliver T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A., Anantidiabetic thiazolidinedione is a high affinity ligand for peroxisomeproliferator-activated receptor gamma (PPAR gamma), J. Biol. Chem.,1995, 270, 12953-6. The ligand binding domains for murine and human PPARalpha, PPAR gamma, and PPAR delta were each fused to the yeasttranscription factor GAL4 DNA binding domain. CV-1 cells weretransiently transfected with expression vectors for the respective PPARchimera along with a reporter construct containing five copies of theGAL4 DNA binding site driving expression of secreted placental alkalinephosphatase (SPAP) and β-galactosidase. After 16 h, the medium wasexchanged to DME medium supplemented with 10% delipidated fetal calfserum and the test compound at the appropriate concentration. After anadditional 24 h, cell extracts were prepared and assayed for alkalinephosphatase and β-galactosidase activity. Alkaline phosphatase activitywas corrected for transfection efficiency using the β-galactosidaseactivity as an internal standard (see, for example, Kliewer, S. A., et.al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL 49653) was used as apositive control in the hPPAR gamma assay. The positive control in thehPPAR alpha assays was2-(2-methyl-3-[3-{3-(4-cyclohexylamino)[6-(4-fluorophenylpiperazin-1-yl)][1,3,5]triazin-2-ylamino}propyl]phenylthio)-2-methylpropionicacid. The positive control for PPAR delta assays was2-{2-methyl-4-[({4-methyl-2-{-{trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid.

All of the above acid Examples showed at least 50% activation of hPPARarelative to the positive control at concentrations of 10⁻⁷ or less.

Activities in three hPPAR subtypes are reported in the table below forthe examples in the acidic form and are expressed in nanomolar.

Examples EC50 hPPAR α EC50 hPPAR δ EC50 hPPAR γ 2 1.7 190 870 4 10 86002224 6 10 1130 10000 8 17 250 1710

1. A compound of formula (I) and pharmaceutically acceptable salts,solvates and hydrolysable esters thereof

wherein R¹ and R² are independently H or C₁₋₃ alkyl or R¹ and R² whichare bonded to the same carbon atom may together with the carbon atom towhich they are bonded form a 3-5 membered cycloalkyl ring; X₁ representsO or S; Each R³, R⁴, R⁸ and R⁹ independently represents H, halogen, —CH₃and —OCH₃; R⁵ represents H or C₁₋₆ alkyl or R⁴ and R⁵ together form a3-6 membered cycloalkyl ring; X₂ represents NH, NCH₃ or O; One of Y andZ is N, and the other is O or S; R⁶ represents phenyl or pyridyl(wherein the N is in position 2 or 3) and is optionally substituted byone or more halogen, CF₃, C₁₋₆ straight or branched alkyl (optionallysubstituted by halogen), with the provision that when R⁶ is pyridyl, theN is unsubstituted; R⁷ represents C₁₋₆alkyl, (optionally substituted byone or more halogens), —C₀₋₆alkyl-5 membered heteroaryl,C₀₋₆alkyl-(O)_(n)-phenyl, wherein n is 0 or 1, with the proviso thatwhen R¹ and R² are methyl, R⁸ and R⁹ are H, R⁵ Is H, then R⁷ cannot beCH₃ or CF₃.
 2. A compound according to claim 1 which is a selectivehPPAR alpha agonist.
 3. A compound according to claim 1 wherein X₁represents O.
 4. A compound according to claim 1 wherein R¹ and R² aremethyl.
 5. A compound according to claim 1 wherein R³ is methyl or H. 6.A compound according to claim 1 wherein R⁴ is H or together with R⁵forms a 6 membered cycloalkyl ring.
 7. A compound according to claim 6wherein R⁸ and R⁹ are H.
 8. A compound according to claim 1 wherein R⁵represents CH₃ or together with R⁴ forms a 6 membered cycloalkyl ring.9. A compound according to claim 1 wherein X₂ represents NH.
 10. Acompound according to claim 1 wherein Z represents N.
 11. A compoundaccording to claim 1 wherein Y represents S.
 12. A compound according toclaim 1 wherein R⁶ is monosubstituted.
 13. A compound according to claim12 wherein R⁶ is monosubstituted in the para position.
 14. A compoundaccording to claim 1 wherein R⁶ is phenyl.
 15. A compound according toclaim 1 selected from the group consisting of:2-methyl-2-[3-methyl-4-{[(4-phenoxymethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester,2-methyl-2-[3-methyl-4-{[(4-phenoxymethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid,2-methyl-2-[3-methyl-4-{[(4-thiophen-2-ylmethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester,2-methyl-2-[3-methyl-4-{[(4-thiophen-2-ylmethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid,2-Methyl-2-[5-{[(4-Methyl-2-[4-trifluoromethyl-phenyl]-thiazol-5-ylcarbonyl)amino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]propionicacid ethyl ester,2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester,2-Methyl-2-[5-{[(4-Methyl-2-[4-trifluoromethyl-phenyl]-thiazol-5-ylcarbony)amino]-5,6,7,8-tetrahydronaphtalen-2-yloxy]propionicacid,2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid, and pharmaceuticallyacceptable salts, solvates and hydrolysable esters thereof.
 16. Acompound selected from the group consisting of2-methyl-2-[3-methyl-4-{1-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionicacid, and pharmaceutically acceptable salts, solvates and hydrolysableesters thereof.
 17. A pharmaceutical composition comprising a compoundaccording to claim
 1. 18. A pharmaceutical composition according toclaim 17 further comprising a pharmaceutically acceptable diluent orcarrier.
 19. A method of treating a hPPAR alpha mediated disease orcondition in a patient wherein the hPPAR alpha mediated disease orcondition is selected from the group consisting of dyslipidemia,syndrome X, heart failure, hypercholesteremia, cardiovascular disease,type II diabetes mellitus, type I diabetes, insulin resistance,hyperlipidemia, obesity, anorexia bulimia and anorexia nervosacomprising the administration of a therapeutically effective amount of acompound according to claim 1.